Repair of O4-alkylthymine damage in human cells.
The capacity of a cell to repair damage is the first step in preventing the deleterious consequences of DNA structural alterations induced by the exposure to mutagenic carcinogens. Mammalian cells, having complex genetic organization, have evolved sophisticated mechanisms for the maintenance of integrity of their genome and normal cell function (Bohr and Hanawalt, 1988; Sancar and Sancar, 1988; Pienta et al., 1989). However, many DNA repair processes in mammalian cells are similar to those in prokaryotic cells. For example, the unique damage reversal mechanism by transferase, specific for the repair of O6-alkylGua, results in the restoration of intact guanine base in both bacteria and mammalian cells (Olsson and Lindahl, 1980; D'Ambrosio and Wani, 1989). The proteins involved, however, are different and vary in their specificities. Mammalian transferase specific for O6-alkylGua, more closely resembles the bacterial ogt gene product (Potter et al., 1987; Rebeck et al., 1988). The main O6-alkylGua specific transferase activity in E. coli resides in the product of the ada gene (Demple et al., 1985; Nakabeppu et al., 1985). This protein possesses multiple activities including a specificity for the transfer of alkyl group from O4-alkylthy in DNA. Such a transferase activity specific for O4-alkylThy has not been detected in mammalian cells either as an individual activity or part of a multi-activity protein (Brent et al., 1988). Nevertheless, there is tangible evidence for the active removal of O4-alkylthy in mammalian cells, particularly human cells. The nature, level, and mode of the O4-alkylThy repair activity has not been fully established. Whether the repair occurs by the well known or some novel mechanism(s) has yet to be determined. Recently Boyle et al., (1987) has provided genetic evidence for an alternate mode of repair of O6-alkylGua in mammalian cells. The human cells, that lack O6-MT activity were able to repair O6-nButylGua in cellular DNA. Additional experiments, with mammalian V79 cell lines, indicated a differential specificity for various alkyl groups. It has been suggested that in these cells the repair occurs by an excision process, which is known to recognize the distortions of the DNA duplex rather than the adduct itself (Sancar and Sancar, 1988). Support for the excision mechanism is also provided by in vitro experiments, showing repair of O6-MeGua by purified E. coli ABC excinuclease enzyme (Voigt et al., 1989). It is quite likely that the repair of O4-alkylThy in mammalian cells occurs by a similar process.(ABSTRACT TRUNCATED AT 400 WORDS)
Wani
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Department of Radiology, Ohio State University, Columbus 43210.
Wani
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D'Ambrosio
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D000477:Alkylating Agents / Q000633:toxicity*; D000478:Alkylation; D002471:Cell Transformation, Neoplastic; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000209:etiology; D013941:Thymine / Q000031:analogs & derivatives* / Q000378:metabolism
D000477:Alkylating Agents; D004247:DNA; D013941:Thymine